This interdisciplinary (Orthopedics and Biochemistry) project is aimed at improving our current knowledge of the metabolic processes involved in the onset and progression of degenerative disc disease and at providing information that may lead to the development of better approaches for the diagnosis, prevention and treatment of this condition. The first aim is to relate early and late degenerative changes detected by magnetic resonance imaging (MRI) of the human spines studied in project I of this program project to changes in the gross and histochemical/immunological appearances as well as the composition and organization of the matrix of IVDs isolated from these spines. With the goal of determining if degenerative changes occurring at specific stages (i.e. early vs late) are associated with specific metabolic changes we will characterize the sequence of progressive changes in gene expression by the NP and AF cells in those discs. The second aim is to develop models of discs degeneration by culturing discs with their endplates or IVD cells that have reestablished a matrix in alginate gel in the presence of interleukin-1 (IL-1). We postulate that, at the doses it has been detected in degenerating human disc tissues, IL-1 will be effective in causing loss of matrix synthesis, principally by shutting down matrix synthesis. We then propose to determine how effective osteogenic protein- 1 (OP- 1) is in promoting the repair of the IL- 1 -treated IVD and its matrix. Metabolic experiments will be performed to identify through what metabolic mechanisms this bone morphogenetic protein promotes the return to and subsequent maintenance of matrix homeostasis.